Peripheral arterial disease (PAD) is caused by atherosclerosis of the leg arteries and is usually complicated by vascular accidents occurring not only in peripheral circulation but also in cerebral and coronary trees. Approximately one third of patients with PAD suffers from claudication, that usually deteriorates slowly: 25% of patients have worsening claudication and about 5% experience amputation within 5 years.
Patients with claudication have severe limitations in exercise capacity due to reduced blood flow in the peripheral circulation. There is evidence that impairment of carnitine function, likely as a consequence of acylcarnitine accumulation, contributes to metabolic changes that facilitate the occurrence of claudication (Hiatt, W R, et al.; J. Clin. Invest,. 1989; 84:1167-73).
Metabolic changes including accumulation of acyl-carnitines with eventual impairment of skeletal muscle metabolism has been reported in claudicant patients (Brass, E P; Hiatt, W R; J. Am. Coll. Nutr.; 1998 Jun; 17(3):207-15). Also, randomised placebo-controlled clinical trials with levocarnitine and propionyl L-carnitine orally given demonstrated a significant increase of walking distance in patients with claudication (Brevetti, G; et al.; J. Am. Coll. Cardiol.; 1995; 26:1411-6; Brevetti, G; et al.; Eur. Heart J.; 1992; 13:251-5; Brevetti, G; et al.; Circulation; 1988; 77:767-73; Brevetti, G; et al.; J. Am. Coll. Cardiol.; 1999; 34.1618-24; Hiatt, W R; et al.; Am. J. Med.; 2001; 110:616-22), suggesting a contributing role of the metabolic status in deteriorating claudication. It was demonstrated that propionyl L-carnitine inhibits arachidonic acid accumulation in the phospholipids of platelet membrane with ensuing reduction of platelet thromboxane A2 and O2 formation (Pignatelli, P; et al.; Am. J. Physiol. Heart Circ. Physiol.; 2003; 284:H41-8). A potential relevance of platelet function on the progression of PAD is known (Hiatt, W R.; N. Engl. J. Med.; 2001; 344:1608-1621).
Studies by Brevetti et al., see also U.S. Pat. No. 4,968,719, provide a limited teaching to the oral administration of L-carnitine or propionyl L-carnitine to a daily dose of 2 g. In particular, Brevetti et al. (Circulation, 1988; 77:767-73) demonstrated that, in six claudicant patients intravenously treated with 3 g L-carnitine as a bolus followed by infusion of 2 mg/Kg/man for 30 minutes, the increase of venous lactate induced by walking test was lowered; but it was not reported if this treatment had some effects on walking distance.
Corsi, U.S. Pat. No. 5,811,457, discloses the use of propionyl L-carnitine in a therapeutic method for the treatment of chronic arteriosclerosis obliterans at stage II of Leriche Fontaine's classification in patients with maximal walking distance (MWD) equal to or greater than 100 meters and shorter than 300 meters.
This reference, makes a better distinction of the patient population affected by peripheral arterial disease with respect to U.S. Pat. No. 4,968,719. The patent enables for an oral administration of 2 g/day of propionyl L-carnitine and shows that a clinical response begins to be clinically evident between the 4th and 6th month of treatment. The whole treatment was protracted for 12 months. The preferred administration route is the oral one and no particular weight is given to other administration routes, given as intended to be equivalent to each other.
All the studies disclosed in the prior art never gave a proper emphasis to the physical exercise of the patient jointly with PLC administration, but only used exercise performance on a treadmill as a methodologic instrument to test the efficacy of drug therapy. Physical exercise is only given as general recommendation to all claudicants in the overall advice to modify the life style. In that context, the recommendation for physical exercise is merged with other medical advices, such as stop smoking. This change in life style is expected to increase MWD.
The state of the art successfully improved the walking distance, a symptomatic parameter, and also improved the physiopathological state of the patient and the quality of life (QoL).
To date, only pharmacological clinical treatment is found effective on symptomatic improvement. Two drugs are use in clinical practice. Cilostazol (Pletal®) is the most effective and actually the most used. However, there are some concerns on its safety (www.fda.gov/cder/-news/cilostazol/approval.htm). Pentoxyfilline (Trental®) is a relatively safer drug, but far less effective and its use is limited.
In spite of all the intense search for an effective therapy for peripheral arterial disease, the need for an improved therapeutic treatment still remains, with particular view for patient's improvement of physiopathological parameters, patient's compliance (due to the treatment period length) and, finally, its safety.
Finally, symptomatic improvement is an aspect of better quality of life (QoL), which through the use of validated instruments, also assesses other realms of daily living, such as emotional status and relationship with others. Examples of validated instruments for QoL are: the Medical Outcome Scale-Short Form 36 (MOS-SF36), the Walking Impairment Questionnaire (WIQ), and others.
The ideal treatment of claudication should affect both objective symptomatic improvement (Walking Distance) and subjective functional status (QoL).